INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 725

BILE

Hepatocyte

Mdr1

Cyp3a

f L Dg3 L Dg2 L Dg1 L Dg0 L

Sinusoidal
Efflux

Oatp1a4

k rp

f p Dg3 p

Dg3-rbc

k pr

Dg3 bound

FIGURE 23.8. Schematic presentation of the fates of digoxin (Dg3) and its metabolites, Dg2
(di-digitoxoside), Dg1 (mono-digitoxoside), and Dg0 (digoxigenin) in the rat liver. Dg3 is
taken up by Oatp1a4 and is excreted via Pgp/Mdr1 into bile. Dg3 is metabolized by Cyp3a to
Dg2, Dg1, and Dg0. (From ref. 96, with permission.)

uptake clearances when estimated as the sum of saturable (CL uptake or V max / K m )
and nonsaturable (PS uptake ) components (Figure 23.9 and Table 23.5). The findings
contrasted with those of others who showed a perivenous abundance of Oatp1a4. 100
Western blotting (Figure 23.5 b ) and confocal immunofluorescent microscopy verified
the lack of zonal distribution of the Oatp1a4. 89 These, when scaled up, provided the
influx clearance (CL influx ) for the transport of digoxin into rat liver. The distribution
of Pgp/Mdr1 in zones 1, 2, and 3 was similar (Figure 23.5 c ). 89
Modeling of the digoxin data (reservoir and bile) from recirculating rat liver per-
fusion studies in the absence of RBCs and albumin at a 40-mL/min flow rate (KHB-
perfused liver), and with 20% RBC-1% albumin at 10 mL/min (RBC-alb-perfused
liver) was successful (Figure 23.10). 89 Normally, the free drug concentration may
be estimated as the unbound fraction multiplied by the total drug concentration.
However, the slow exchange of digoxin between plasma and RBCs (Figure 23.8)
necessitated consideration of these binding-debinding rate constants in the ZPBPK
model (Figure 23.3 b ). The exchange-rate constants from plasma to RBCs ( k pr or
0.468 0.12 min − 1 )of

digoxin demonstrate a slow (RBC) distribution and modest plasma protein binding
(an unbound plasma fraction of 0.64). 89 The slow efflux from RBCs may constitute
an impediment to drug removal. 101 To enable fitting, the uptake clearance CL influx ,
provided by scale-up of hepatocyte uptake data (Table 23.5), and the parameters on
RBC partitioning ( k pr and k rp ) and digoxin binding in plasma (an unbound fraction in
f p ) were assigned. The values of CL influx , i ,CL efflux , i , and CL int , sec , i were partitioned
evenly for each zone (one-third of the value of the liver), whereas that for CL int , met , i
for metabolism by Cyp3a2 for zones 1, 2, and 3, respectively, was assigned arbitrarily

0.021 min − 1 ) and from RBCs to plasma ( k rp

± or 1.81 ±